Establishment of a blood-free environment is a prerequisite in reconstructive and orthopedic surgery, which is commonly achieved by tourniquet application. The deprivation of blood and oxygen, termed as ischemia, leads to time-dependent molecular and structural changes of the affected tissue. Complex inflammatory cascades, like the complement, coagulation, as well as the plasma kallikrein-kinin system, are then activated when blood flow is restored, leading to ischemia/reperfusion injury (IRI). Tourniquet-induced IRI is manifested in edema formation, loss of muscle viability and apoptosis, which significantly affects the outcome of surgical interventions. Furthermore, IRI is known to induce a local as well as a systemic inflammatory response leading to remote tissue and organ damage, a phenomenon which is well known in the clinics. Until now, there are no agents available in the clinics to treat local as well as systemic inflammatory responses after IRI (1).
The natural complement inhibitor C1 esterase inhibitor (C1INH) has been demonstrated to inhibit all three complement pathways (classical, lectin as well as the alternative pathway), the coagulation system as well as the kallikrein-kinin system (2-4). Plasma-derived C1INH is successfully used in the clinics to treat C1INH deficient patients suffering from hereditary angioedema (HAE) (2). Several animal studies have demonstrated a therapeutic potential of plasma-derived C1INH on local IRI, namely solid organ transplantation, myocardial infarction, stroke, hepatic and intestinal IRI (4). Two different studies demonstrated a potential therapeutic effect of plasma-derived C1INH on local skeletal muscle IRI, attributing the effect to the complement system (5,6). A study using transgenic mice overexpressing human C1INH with “supraphysiologically” high plasma levels showed a reduction of remote organ damage in lung and skeletal muscle in a model of lower torso IRI (7). However, in this model C1INH was constitutively expressed, including during embryonic development, which may lead to changes in the physiology and pathophysiological reactivities. So far, no effect of plasma-derived C1INH on IRI-induced remote tissue or organ damage has been demonstrated.
Surprisingly, using a rat animal model of tourniquet-applied hind limb IRI, the inventors could demonstrate a therapeutic effect of plasma-derived C1INH not only on local but also on remote tissue and organ damage. For example, a significant reduction of lung edema was observed. C1INH plays a major role in inhibiting the contact activation system, and its effect on remote tissue and organ damage indicates a major pathophysiological role of the components of this system not only on local tissue and organ damage but also on the remote damage observed during IRI. The results indicate that substances targeting the contact activation system, such as C1INH, kallikrein inhibitors or Factor XII (FXII) inhibitors, ameliorate or even prevent remote tissue and organ damage.